Helicobacter pylori infection is the major etiological factor in the development of gastritis, gastric ulcers, and gastric carcinoma. About 50% of the world's population is infected with H. pylori and H. pylori infection presents a major global publi health burden. Eradication of H. pylori with more than one antibiotic is recommended for infected patients and has become the first line treatment for H. pylori infection. While antibiotic therapy is effective in eradicating H. pylori infection, its efficacy is gradually decreasing. Antibiotic resistance is the major cause of treatment failure and has become the most evident challenge to treatment of H. pylori infection. It is urgently required to develop novel therapies that are able to eradicate H. pylori but not easily susceptible to resistance. Synthetic antimicrobial oligo peptides (AMP) have recently emerged as novel antimicrobial agents in combating multidrug resistant microbes. However, the microbiocidal activity of these peptides on H. pylori has rarely been tested. The overall goal of this proposal is to design a new class of polypeptides that would selectively kill H. pylori under acidic conditions and explore their therapeutic potentials in eradication of H. pylori infection and its associated gastric diseases. n Specific Aim 1, we will determine the anti-microbial activity of polypeptides with unique helical structure. We will design and develop polypeptides that can be converted from a non-helical structure to a helical structure under acidic pH to selectively kill H. pylori. In Specific Aim 2, e will explore the anti-microbial potential of these pH-activated polypeptides in eradication of H. pylori infection and H. pylori-induced gastric diseases. We will also determine the bactericidal activity of these peptides toward antibiotic-resistant H. pylori strains. These in vitro, cell-base, and in vivo animal experiments will provide new insights into the development of polypeptides as effective agents for eradication of H. pylori infection and also provide new information on nontraditional therapy for the eradication of H. pylori infection and the prevention H. pylori- mediated gastric diseases.